Plaster containing felbinac

ABSTRACT

A plaster comprising a styrene-isoprene-styrene block copolymer 10-40 wt %, a rosin-based resin 5-30 wt %, a plasticizer 20-70 wt %, polyisobutylene 6-40 wt %, an antioxidant 0.1-5 wt %, and felbinac as a medicinally effective component 1.1-10 wt %, wherein the plaster does not contain crotamiton which is a solubilizer for the felbinac, the felbinac is uniformly dispersed in a semi-solubilized state in the plaster, wherein solubilized felbinac and microcrystalline felbinac coexist in the plaster, and a thickness of the plaster is 50-300 μm.

CROSS-REFERENCED APPLICATIONS

This application is a divisional of application Ser. No. 09/859,516,filed May 18, 2001 issued as U.S. Pat. No. 6,620,430, which is acontinuation-in-part of application Ser. No. 09/297,643, filed May 5,1999 now abandoned, which is the U.S. National phase of InternationalApplication PCT/JP97/04439, filed December 4, 1997, and the completedisclosures of such prior applications are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a plaster containing felbinac and, moreparticularly, to an anti-inflammatory, analgesic plaster containingfelbinac of an anti-inflammatory, analgesic agent as a medicinallyeffective component for the purpose of curing lumbago, myalgia,periarthritis, and so on.

2. Related Background Art

Felbinac (4-biphenylacetic acid) is an active metabolite of fenbufen, anon-steroid type anti-inflammatory, analgesic agent, and is a drugdemonstrating strong anti-inflammatory and analgesic actions. Since thisdrug is not suitable for oral administration, the attention has beenfocused on studies on preparations for dermal administration. Gels,liquids, and poultices containing the above-stated drug are commerciallyavailable hitherto. The gels and liquids, however, had problems ofdifficulty in administration in a given quantity, low bioavailability,adhesion to clothing, a number of administrations (for example, severaladministrations per day), and so on. The poultices have been developedin order to overcome these problems of the gels and liquids, but theystill had problems of incapability of affixing them for a long period oftime because of their weak adhesion, low bioavailability, andinsufficient persistence of the effect of the drug. Japanese PatentApplication Laid-Open Gazette No. Hei. 4-321624 proposed ananti-inflammatory, analgesic plaster in which the chief component of thebase was a styrene-isoprene-styrene block copolymer and in whichcrotamiton was an essential solubilizer.

SUMMARY OF THE INVENTION

The inventors, however, found that the anti-inflammatory, analgesicplaster described in the Laid-Open Gazette No. Hei. 4-321624 was not yetsatisfactory when felbinac was used as an anti-inflammatory, analgesicagent, as described below. Namely, the anti-inflammatory, analgesicplaster described in above Laid-Open Gazette No. Hei. 4-321624 was notyet satisfactory in that work steps were cumbersome because of the useof crotamiton as a solubilizer for the drug and in that secular decreasein adhesion occurred due to bleeding (percolating to the surface) ofcrotamiton.

Further, U.S. Pat. No. 5,725,874 proposed a plaster comprising felbinac,a styrene-isoprene-styrene block copolymer, a rosin ester derivative, aplasticizer and polyisobutylene as shown in Examples 36 and 37. However,the plaster disclosed in U.S. Pat. No. 5,725,874 comprised3-1-menthoxypropane-1,2-diol as an essential solubilizer. The drugs(pharmaceutically effective ingredients including felbinac) in theplaster disclosed in U.S. Pat. No. 5,725,874 existed in fullysolubilized or molten state. This was also apparent from the fact thatthe plasters of Examples 36 and 37 disclosed in U.S. Pat. No. 5,725,874contained 3-1-menthoxypropane-1,2-diol in an amount of 5.0-7.0 wt %which was larger than that of felbinac (2.0 wt %) The plaster disclosedin U.S. Pat. No. 5,725,874 was not yet satisfactory in that the plasterwas insufficient in discharge stability of the drug and in durability ofthe pharmacological action.

The present invention has been accomplished in view of the problems ofthe prior art described above and an object of the invention is toprovide a plaster containing felbinac that can maintain the adhesion toskin in a high level over a long period of time, that is safe with lessirritation of skin, that is excellent in stability of preparations, andthat is high in release ability of the drug and excellent in theanti-inflammatory action, thus retaining the effect of the drug for along period of time.

The inventors conducted extensive and intensive studies to achieve theabove object and attained the following knowledge, thus completing thepresent invention. Specifically, those skilled in the art consideredbefore that, because the drug existed in a crystalline state in thedispersion type plasters containing no solubilizer, percutaneousabsorption of the drug must be small to expect the sufficient effect. Inspite thereof, the present inventors found that a felbinac-containingplaster containing specific components in a specific composition andhaving a specific thickness, which is a dispersion type plastercontaining no solubilizer and containing felbinac in a semi-solubilizedstate, had high drug release ability, retained the sufficient,pharmacological action for a long period of time, maintained theadhesion to skin in a high level for a long period of time, and wasexcellent in stability of preparations and less in the skin irritation,thus accomplishing the present invention.

The felbinac-containing plaster according to the present invention is aplaster comprising a styrene-isoprene-styrene block copolymer 10-40 wt%, a rosin-based resin 5-30 wt %, a plasticizer 20-70 wt %,polyisobutylene 6-40 wt %, an antioxidant 0.1-5 wt %, and felbinac as amedicinally effective component 1.1-10 wt %, wherein said plaster doesnot contain crotamiton which is a solubilizer for said felbinac, saidfelbinac is uniformly dispersed in a semi-solubilized state in saidplaster, wherein solubilized felbinac and microcrystalline felbinaccoexist in said plaster, and a thickness of said plaster is 50-300 μm.

Further, the felbinac-containing plaster according to the presentinvention preferably consists essentially of a styrene-isoprene-styreneblock copolymer 10-40 wt %, a rosin-based resin 5-30 wt %, a plasticizer20-70 wt %, polyisobutylene 6-40 wt %, an antioxidant 0.1-5 wt %, andfelbinac as a medicinally effective component 1.1-10 wt %, wherein saidplaster does not contain crotamiton which is a solubilizer for saidfelbinac, said felbinac is uniformly dispersed in a semi-solubilizedstate in said plaster, wherein solubilized felbinac and microcrystallinefelbinac coexist in said plaster, and a thickness of said plaster is50-300 μm.

The present invention will become more fully understood from thedetailed description given hereinbelow and the accompanying drawingswhich are given by way of illustration only, and thus are not to beconsidered as limiting the present invention.

Further scope of applicability of the present invention will becomeapparent from the detailed description given hereinafter. However, itshould be understood that the detailed description and specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an electron microscope photograph (×100) of the plasterobtained in Example 5.

FIG. 2 is an electron microscope photograph (×500) of the plasterobtained in Example 5.

FIG. 3 is a graph to show the results of skin permeation experimentusing hairless mice.

FIG. 4 is a graph to show the results of carrageenin-induced paw edemaexperiment in rabbits.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the felbinac-containing plaster according to the present invention,felbinac as a medicinally effective component is contained in a specificblending ratio in the base containing the styrene-isoprene-styrene blockcopolymer, the rosin-based resin, the plasticizer, polyisobutylene andthe antioxidant in specific blending ratios, respectively. First, thevarious base components used for forming the plaster of the presentinvention will be described in detail.

The styrene-isoprene-styrene block copolymer according to the presentinvention is a block copolymer of styrene and isoprene and haspolystyrene chains at the both ends, and this styrene-isoprene-styreneblock copolymer can be selected from Califlex TR-1107, TR-1111, TR-1112or TR-1117 (trade names, available from Shell Kagaku K. K.), JSRSIS-5000 or 5002 (trade names, available from Japan Synthetic RubberCo., Ltd.), Quintac 3530 or 3421 (trade names, available from NipponZeon Co., Ltd.), Solprene 428 (trade name, available from PhillipsPetroleum International Ltd.), and so on, which can be used singly or ina combination of two or more species.

A blending ratio of the styrene-isoprene-styrene block copolymer is10-40 wt % and preferably 15-35 wt % of the whole plaster. This range ofblending ratio demonstrates great improvements in stability ofpreparations (the plaster), adhesive strength (tackiness), the adhesionto skin in the long term (adhesion persistence), percutaneous absorptionof the drug, dispersibility of the drug, pain upon stripping, the rateof occurrence of eruptions in the skin, and so on. In a case where theabove blending ratio is lower than 10 wt %, cohesive force and shaperetention of the base will degrade. On the other hand, blending ratiosover 40 wt % will cause reduction in adhesive strength, nonuniformity ofointment (plaster), and degradation of workability.

The rosin-based resin according to the present invention is a resincontaining rosin or a rosin derivative as a base material, and thosesuitably applicable are rosin esters, hydrogenated rosin esters, maleicrosins, and so on. The rosin-based resin can be selected from Ester GumA, AA-G, H or HP (trade names, available from Arakawa ChemicalIndustries Ltd.), Hariester L, S or P (tradenames, available fromArakawa Chemical Industries Ltd.), Pinecrystal KE-100 (trade name,available from Arakawa Chemical Industries Ltd.), KE-311 (trade name,available from Arakawa Chemical Industries Ltd.), Hercolyn D (tradename, available from Rika-Hercules Inc.), Foral 85 or 105 (trade names,available from Rika-Hercules Inc.), Stebelite Ester 7 or 10 (tradenames, available from Rika-Hercules Inc.), Pentalyn 4820 or 4740 (tradenames, available from Rika-Hercules Inc.), and so on, which can be usedsingly or in a combination of two or more species.

A blending ratio of the above rosin-based resin is 5-30 wt % andpreferably 10-25 wt % of the whole plaster. This range of blending ratioexhibits great improvements in the stability of preparations, adhesivestrength, adhesion persistence, percutaneous absorption of the drug,dispersibility of the drug, pain upon stripping, the rate of occurrenceof eruptions in the skin, and soon. Blending ratios below 5 wt % willdegrade the adhesive strength, adhesion persistence, and dispersibilityof the drug and cause nonuniformity of ointment and degradation ofworkability due to increase in the viscosity of ointment. On the otherhand, blending ratios over 30 wt % will degrade the percutaneousabsorption of the drug and shape retention and will increase the painupon stripping, the rate of occurrence of eruptions in the skin,stickiness, and so on.

The plasticizer according to the present invention is an agentcompatible with the other base components and capable of providing thebase with flexibility, and suitably applicable plasticizers are almondoil, olive oil, tsubaki oil, persic oil, peanut oil, olefin acids,liquid polyisoprene, liquid polybutene, liquid paraffin, and so on.These plasticizers may be used singly or in a combination of two or morespecies and among them the liquid paraffin is particularly preferred.

A blending ratio of the above plasticizer is 20-70 wt % and preferably30-60 wt % of the whole plaster. This range of blending ratio exhibitsgreat improvements in the stability of preparations, adhesive strength,adhesion persistence, percutaneous absorption of the drug,dispersibility of the drug, pain upon stripping, the rate of occurrenceof eruptions in the skin, and so on. Blending ratios below 20 wt % willdegrade the adhesive strength, percutaneous absorption of the drug, anddispersibility of the drug and will cause nonuniformity of ointment anddegradation of workability due to increase in the viscosity of ointment.On the other hand, blending ratios over 70 wt % will degrade thestability of preparations, cohesive force, and shape retention and willincrease the pain upon stripping, stickiness, and so on.

The plaster of the present invention further comprises polyisobutylene,in addition to the aforementioned styrene-isoprene-styrene blockcopolymer, rosin-based resin, plasticizer, and felbinac, and thus it maybe substantially comprised of the styrene-isoprene-styrene blockcopolymer, rosin-based resin, plasticizer, polyisobutylene, andfelbinac.

The polyisobutylene according to the present invention is a polymer ofisobutylene and the polyisobutylene is selected from Opanol B-3, B-10,B-15, B-50, B-100 or B-200 (trade names, available from BASFAG),Vistanex LM-MS, LM-MH, MML-80, MML-100, MML-120 or MML-140 (trade names,available from Exxon Chemical Japan Ltd.), Tetrax 3T, 4T, 5T or 6T(trade names, available from Nippon Petrochemicals Co., Ltd.), and soon, which can be used singly or in a combination of two or more species.

A blending ratio of the above polyisobutylene is 6-40 wt % andpreferably 6.5-20 wt % of the whole plaster. This range of blendingratio will reveal improvements in the stability of preparations,adhesive strength, adhesion persistence, percutaneous absorption of thedrug, dispersibility of the drug, pain upon stripping, the rate ofoccurrence of eruptions in the skin, and soon. Blending ratios below 6wt % will tend to degrade the adhesive strength and adhesion persistenceand increase the pain upon stripping and the rate of occurrence oferuptions in the skin. On the other hand, blending ratios over 40 wt %will tend to degrade the shape retention and increase the stickiness.

The plaster of the present invention further contain an antioxidant, inaddition to the aforementioned styrene-isoprene-styrene block copolymer,rosin-based resin, plasticizer, felbinac and polyisobutylene.Accordingly, the plaster of the present invention may be substantiallycomprised of the styrene-isoprene-styrene block copolymer, rosin-basedresin, plasticizer, polyisobutylene, antioxidant, and felbinac.

The antioxidant according to the present invention is selected fromascorbic acid, propyl gallate, butylhydroxyanisole,dibutylhydroxytoluene (BHT), nordihydroguaiaretic acid, tocopherol,tocopherol acetate, and so on.

A blending ratio of the antioxidant is 0.1-5 wt % and preferably 0.5-2wt % of the whole plaster. Blending ratios below the lower limit willtend to cause deterioration of the base with a lapse of time andincrease remainder of ointment, stickiness, and so on. On the otherhand, blending ratios over the upper limit will tend to degrade thecohesive force of preparations and the shape retention and increase thepain upon stripping, stickiness, and so on.

In the plaster of the present invention, felbinac as a medicinallyeffective component, i.e., 4-biphenylacetic acid, is contained in thespecific blending ratio in the base containing the aforementionedstyrene-isoprene-styrene block copolymer, rosin-based resin,plasticizer, polyisobutylene and antioxidant. The blending ratio offelbinac in the plaster of the present invention is 1.1-10 wt %,preferably 2-8 wt %, and particularly preferably 3-7 wt % of the wholeplaster. This range of blending ratio will exhibit great improvements inthe percutaneous absorption of the drug, persistence of the effect ofthe drug, dispersibility of the drug, and so on. Blending ratios below1.1 wt % will degrade the percutaneous absorption of the drug andpersistence of the effect of the drug and fail to achieve the sufficienteffect of the drug. On the other hand, blending ratios over 10 wt % willdegrade the dispersibility of the drug and cause the nonuniformity ofointment.

The plaster of the present invention contains the felbinac describedabove, but does not contain any crotamiton, which is a solubilizer usedto be conventionally considered as an essential component. Namely, theplaster of the present invention contains the aforementionedstyrene-isoprene-styrene block copolymer, rosin-based resin,plasticizer, polyisobutylene, antioxidant and felbinac and does notcontain any crotamiton being the solubilizer for the felbinac, and itmay be substantially comprised of the styrene-isoprene-styrene blockcopolymer, rosin-based resin, plasticizer, polyisobutylene, antioxidantand felbinac.

Since the felbinac-containing plaster of the present invention containsno crotamiton of solubilizer as described above, secular decrease inadhesive strength will not occur due to the bleeding of crotamiton andit is free of cumbersome work steps caused by use thereof. Thefelbinac-containing plaster of the present invention preferably containsnone of solubilizers for felbinac at all; that is, the plaster,preferably, does not contain any agent capable of apparently dissolvingfelbinac over its solubility in the base at all. When the plaster doesnot contain any other plasticizer than crotamiton, either, as described,there is such a tendency as to prevent occurrence of secular decrease inadhesive strength due to bleeding of solubilizer more certainly.Examples of such solubilizers other than crotamiton are benzyl alcoholand diisopropanolamine.

Although the plaster of the present invention having the abovecomposition does not contain crotamiton being the solubilizer describedabove, felbinac is not taken in a perfectly crystalline state into thebase, but it is uniformly dispersed in a semi-solubilized (semi-molten)state in the base, wherein solubilized felbinac and microcrystallinefelbinac coexist in the plaster. This dispersion provides substantialbenefits, because as the partially solubilized drug (felbinac) isdischarged from the base, the uniformly dispersed drug in thecrystalline state will be dissolved into the base as occasion demands.This provides stable discharge of the drug at constant speed over a longtime in the plaster of the present invention. Therefore, although thedrug does not exist in the fully solubilized state with the solubilizerin the base, different from the solubilizer-containing plaster describedin the Laid-Open Gazette No. Hei. 4-321624, the felbinac-containingdispersion type plaster of the present invention provides high releasingability of the drug and retains sufficient pharmacological action (ananti-inflammatory action) over a long time.

In the plaster of the present invention, a ratio of microcrystallinefelbinac is preferably 20-80 wt % of the whole felbinac (the totalamount of solubilized felbinac and microcrystalline felbinac), at leastin an initial state.

The plaster of the present invention may further contain, if desired,another (other) additive component(s) such as an inorganic filler, asynthetic polymer, a tackifier, an ultraviolet light absorber, anantihistamic agent, an antibacterial agent, or a perfume, in addition tothe aforementioned styrene-isoprene-styrene block copolymer, rosin-basedresin, plasticizer, felbinac, and, if necessary, the polyisobutylene.

The further additive component described above is selected frominorganic fillers (aluminum hydroxide, aluminum silicate hydrate,synthetic aluminum silicate, kaolin, titanium oxide, talc, zinc oxide,silica hydrate, magnesium carbonate, calcium hydrogen phosphate,magnesium silicate, diatomaceous earth, silicic anhydride, bentonite,etc.), synthetic polymers (polyacrylic polymers, synthetic polyisoprenerubbers, polystyrenes, polybutadiene rubbers, silicone rubbers,styrene-butylene-styrene block copolymers, styrene-isoprene blockcopolymers, etc.), tackifiers (terpene resins, petroleum resins, etc.),ultraviolet light absorbers (paraminobenzoic acid, paraminobenzoicester, amyl paradimethylaminobenzoate, salicylic ester, methylanthranilate, umbelliferone, esculin, benzyl cinnamate, cinoxate,guaiazulene, urocanic acid, 2-(2-hydroxy-5-methyphenyl) benzotriazole,4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone, octabenzone,dioxybenzone, dihydroxydimethoxybenzophenone, sulisobenzone,benzoresorsinol, octyl dimethylparamino benzoate, ethylhexylp-methoxy-cinnamate, etc.), antihistamines (isopentyl chloride,diphenhydramine hydrochloride, iproheptine hydrochloride,diphenylpyraline hydrochloride, cyproheptadine hydrochloride,triprolidine hydrochloride, promethazine hydrochloride,homochlorcyclizine hydrochloride, alimemazine tartrate, diphenhydraminetannate, diphenylpyraline piprinhydrinate, clemastine fumarate,chlorpheniramine meleate, dimethindene maleate, mequitazine, etc.),antibacterial agents (paraoxybenzoic ester, benzoic acid, benzoate,salicylate, sorbic acid, sorbate, dehydroacetate,4-isopropyl-3-methylphenol, 2-isopropyl-5-methylphenol, hinokitiol,cresol, 2, 4, 4-trichloro-2′-hydroxydiphenylether, 3, 4,4′-trichlorocarbanilide, chlorobutanol, benzalkonium chloride,benzethonium chloride, etc.), refrigerants or perfumes (1-menthol,etc.), and so on.

A blending ratio of such further additive component is preferably 0.01-7wt % and more preferably 0.1-5 wt % of the whole plaster. Blendingratios below the lower limit will tend to cause deterioration of thebase with a lapse of time and increase remainder of ointment,stickiness, and so on. On the other hand, blending ratios over the upperlimit will tend to degrade the cohesive force of preparations and theshape retention and increase the pain upon stripping, stickiness, and soon.

The thickness (not including thicknesses of a backing and a releasedliner described hereinafter) of the plaster (the plaster layer) of thepresent invention prepared using the above components is 50-300 μm andpreferably 80-200 μm. When the thickness is determined in this range,great improvements are achieved in the adhesive strength, cohesiveforce, adhesion persistence, pain upon stripping, and so on. In a casewhere the above thickness is less than 50 μm, the adhesive strength andadhesion persistence will degrade. On the other hand, in a case wherethe above thickness is over 300 μm, the cohesive force and shaperetention will degrade.

The plaster of the present invention as described above is highlyflexible and freely expands and contracts longitudinally and laterally.Since the plaster of the present invention has the excellent adhesionand high expansion rate as described, it permits use of a highlyflexible backing (support), which was hardly used for the conventionalsolubilizer-containing plasters, and it achieves the affixing feeling ofhigh level.

The felbinac-containing plaster of the present invention described abovehas various excellent characteristics below.

1) Since the plaster is an oil-based plaster, it has excellent adhesionand it can be affixed to even a bending portion such as an elbow or aknee over a long period of time without peeling off.

2) Since the drug is dispersed in a concentration over the solubilitythereof in the semi-solubilized state, the expected effect of the drugappears over a long period of time.

3) Since the plaster has the oil base containing no water, it has anexcellent heat reserving effect of affixed portion and can be used forchronic inflammation and the like.

4) Since the plaster is made without using any solubilizer,absorbefacient agent, or the like, the work steps are easy and simple,and secular stability of preparations is also excellent.

5) The oil-based plaster allows the thickness to be decreased and isexcellent in fit feeling when affixed.

6) The adhesive strength of the conventional solubilizer-containingplasters was not sufficient, and the size thereof was limited toapproximately 80 cm² or less. In contrast with it, the plaster of thepresent invention has the extremely high adhesive strength, because itcontains no solubilizer. Therefore, the size of the present plaster canbe 100 cm² or more. The plaster of the present invention can be made inthe size equivalent to that of the conventional poultices as described,and it is superior in the adhesive strength and flexibility to thepoultices.

The plaster of the present invention described above is preferablyspread on a backing (support). The backing is desirably one notaffecting discharge of the drug from the plaster of the presentinvention and can be flexible or non-flexible. The backing applicable tothe present invention is one selected from a film, a sheet, a sheetporous body, a sheet foam, and a woven or nonwoven fabric of a syntheticresin such as polyethylene, polypropylene, polybutadien, anethylene-vinyl acetate copolymer, polyvinyl chloride, a polyester, apolyamide, or a polyurethane; paper; fabric; nonwoven fabric; alamination thereof, and so on.

Among these plaster backings, a backing with flexibility is preferredand a stretch polyester fabric is particularly suitable. The stretchpolyester fabric is preferably one exhibiting the longitudinal strengthof 200 g to 3 kg and the lateral strength of 100 g to 600 g in the30%-modulus (tensile strength) test under such measurement conditionsthat the sample width is 50 mm, the sample length 200 mm, and theelongation strength 200 mm/min. Further, the basic weight (weight perunit area) of the backing according to the present invention ispreferably 100±30 g/m².

Since the plaster of the present invention has the high expansion rateas described above, it becomes possible to use the backing with highflexibility, which was hardly used for the conventionalsolubilizer-containing plasters, and particularly preferably to use thestretch polyester fabric. Use of the polyester fabric with flexibilityas described tends to make the plaster of the present invention superiorin the following respects. Specifically, i) the conventionalsolubilizer-containing plasters, when affixed to a bending portion suchas a joint to move heavily, were easy to peel off because of the motion.In contrast with it, in the plaster of the present invention, thepolyester fabric can expand and contract longitudinally and laterally inaccordance with the motion of skin, so that the plaster is firmlyaffixed with less stretched feeling and over a long time. ii) Since thepolyester fabric has moderate flexibility, the plaster is easy to affixand easy to strip. iii) The anchoring effect is enhanced (the ointmentpermeates the backing and the adhesive strength is retained), and theflexibility is retained.

A preferred example of a method for preparing the felbinac-containingplaster of the present invention will be described below.

First, a styrene-isoprene-styrene block copolymer, a rosin-based resin,a plasticizer, polyisobutylene and an antioxidant (other additivecomponents, etc. if any) are mixed each in predetermined percentage toobtain a mixture, and the mixture is heated and stirred under an inertatmosphere of nitrogen or the like, thus obtaining a dissolvedsubstance. The temperature upon stirring is preferably 110-200° C. andthe stirring time is preferably 30-120 minutes. Subsequently, felbinacof the effective component is added to the above dissolved substance andthe mixture is stirred preferably at 110-200° C. and preferably for 5-30minutes, thereby obtaining a uniform dispersion.

Then this dispersion is spread directly over the backing (support) by anordinary method and thereafter is covered by a released liner (peelingcover); or, it is also possible to once spread this dispersion over thereleased liner, thereafter place them on the backing, and press andtransfer the dispersion onto the backing. The released liner of thistype is selected from released paper processed by a release treatment (atreatment for facilitating release); cellophane; or a plastic film ofpolyethylene, polypropylene, polyester, or the like; andsoon. The abovepreparation method allows us to obtain the plaster of the presentinvention in which felbinac is uniformly dispersed in thesemi-solubilized state in the base.

It should be noted that only one embodiment was described of the orderof blending of the respective base components, the medicinally effectivecomponent, and the other additive components in the above preparationmethod and that the preparation method of the plaster of the presentinvention is not limited to this method of the blending order.

EXAMPLES

The felbinac-containing plaster of the present invention will bedescribed in more detail with examples and comparative examples, but itshould be noted that the felbinac-containing plaster of the presentinvention is not limited to those described in the following examples.In the examples and comparative examples, “part(s)” and “%” mean“part(s) by weight” and “% by weight”, respectively, unless otherwisestated specifically.

Example 1

styrene-isoprene-styrene block copolymer 25.0 parts (trade name:Califlex TR-1107) liquid paraffin 47.0 parts rosin-based resin 12.0parts (trade name: Ester Gum H) polyisobutylene 10.0 parts (trade name:Opanol B-10) dibutylhydroxytoluene 1.0 part felbinac 5.0 parts

The plaster was prepared in the above formulation according to theaforementioned preparation method. Specifically, the components otherthan felbinac in the above formulation were mixed to obtain a mixtureand the mixture was stirred at 130-180° C. under the nitrogen atmospherefor 40-90 minutes to obtain a dissolved substance. Subsequently,felbinac which is the medicinally effective component was added into thedissolved substance and the mixture was stirred at 130-180° C. for 3-20minutes to obtain a uniform dispersion. Then this dispersion was spreadover the backing (fabric of polyester) so that the thickness of theplaster layer obtained was 50 μm. Thereafter, the dispersion was coveredby the released liner (polyester film) and the product after cooled wascut in the desired size, thereby obtaining the dispersion type plasterin which felbinac was uniformly dispersed in the semi-solubilized state.The polyester fabric used was one having the longitudinal strength of210-300 g and the lateral strength of 100-170 g in the 30%-modulus test(the sample width 50 mm, the sample length 200 mm, and the elongationstrength 200 mm/min, using Autograph AGS-100B (available from ShimadzuCorporation), and having the basic weight of 110±20 g/m².

Example 2

styrene-isoprene-styrene block copolymer 30.0 parts (trade name:Califlex TR-1111) liquid paraffin 39.0 parts rosin-based resin 20.0parts (trade name: Pinecrystal KE-100) polyisobutylene 6.0 parts (tradename: Opanol B-50) dibutylhydroxytoluene 1.0 part felbinac 4.0 parts

The plaster was prepared in the same manner as in Example 1 except thatthe formulation was changed to the above formulation and that thethickness of the plaster layer was 100 μm, obtaining the dispersion typeplaster in which felbinac was uniformly dispersed in thesemi-solubilized state.

Example 3

styrene-isoprene-styrene block copolymer 20.0 parts (trade name:Califlex TR-1112) liquid paraffin 46.0 parts rosin-based resin 15.0parts (trade name: Stebelite Ester 7) polyisobutylene 15.0 parts (tradename: Opanol B-100) dibutylhydroxytoluene 1.0 part felbinac 3.0 parts

The plaster was prepared in the same manner as in Example 1 except thatthe formulation was changed to the above formulation and that thethickness of the plaster layer was 140 μm, obtaining the dispersion typeplaster in which is felbinac was uniformly dispersed in thesemi-solubilized state.

Example 4

styrene-isoprene-styrene block copolymer 23.0 parts (trade name:Califlex TR-1117) liquid paraffin 40.0 parts rosin-based resin 25.0parts (trade name: KE-311) polyisobutylene 8.0 parts (trade name: OpanolB-200) dibutylhydroxytoluene 1.0 part felbinac 3.0 parts

The plaster was prepared in the same manner as in Example 1 except thatthe formulation was changed to the above formulation and that thethickness of the plaster layer was 300 μm, obtaining the dispersion typeplaster in which felbinac was uniformly dispersed in thesemi-solubilized state.

Example 5

styrene-isoprene-styrene block copolymer 20.0 parts (trade name: JSRSIS-5000) liquid paraffin 41.0 parts rosin-based resin 15.0 parts (tradename: Foral 105) polyisobutylene 20.0 parts (trade name: Vistanex LM-MS)dibutylhydroxytoluene 1.0 part felbinac 3.0 parts

The plaster was prepared in the same manner as in Example 1 except thatthe formulation was changed to the above formulation and that thethickness of the plaster layer was 200 μm, obtaining the dispersion typeplaster in which felbinac was uniformly dispersed in thesemi-solubilized state. Electron microscope photographs (×100 and ×500)of the plaster obtained in Example 5 are shown as FIGS. 1 and 2.

Example 6

styrene-isoprene-styrene block copolymer 15.0 parts (trade name: JSRSIS-5002) liquid paraffin 58.0 parts rosin-based resin 15.0 parts (tradename: Stebelite 10) polyisobutylene 7.0 parts (trade name: VistanexLM-MH) dibutylhydroxytoluene 1.0 part felbinac 4.0 parts

The plaster was prepared in the same manner as in Example 1 except thatthe formulation was changed to the above formulation and that thethickness of the plaster layer was 80 μm, obtaining the dispersion typeplaster in which felbinac was uniformly dispersed in thesemi-solubilized state.

Example 7

styrene-isoprene-styrene block copolymer 35.0 parts (trade name: Quintac3530) liquid paraffin 35.0 parts rosin-based resin 15.0 parts (tradename: Foral 85) polyisobutylene 10.0 parts (trade name: VistanexMML-140) dibutylhydroxytoluene 1.0 part felbinac 4.0 parts

The plaster was prepared in the same manner as in Example 1 except thatthe formulation was changed to the above formulation and that thethickness of the plaster layer was 160 μm, obtaining the dispersion typeplaster in which felbinac was uniformly dispersed in thesemi-solubilized state.

Example 8

styrene-isoprene-styrene block copolymer 25.0 parts (trade name: Quintac3421) liquid paraffin 30.0 parts rosin-based resin 22.0 parts (tradename: Pentalyn 4820) polyisobutylene 15.0 parts (trade name: Tetrax 3T)dibutylhydroxytoluene 1.0 part felbinac 7.0 parts

The plaster was prepared in the same manner as in Example 1 except thatthe formulation was changed to the above formulation and that thethickness of the plaster layer was 120 μm, obtaining the dispersion typeplaster in which felbinac was uniformly dispersed in thesemi-solubilized state.

Example 9

styrene-isoprene-styrene block copolymer 25.0 parts (trade name:Solprene 428) liquid paraffin 36.0 parts rosin-based resin 25.0 parts(trade name: Hercolyn D) polyisobutylene 7.5 parts (trade name: Tetrax5T) dibutylhydroxytoluene 1.0 part 1-menthol 0.5 part felbinac 5.0 parts

The plaster was prepared in the same manner as in Example 1 except thatthe formulation was changed to the above formulation and that thethickness of the plaster layer was 160 μm, obtaining the dispersion typeplaster in which felbinac was uniformly dispersed in thesemi-solubilized state.

Example 10

styrene-isoprene-styrene block copolymer 15.0 parts (trade name: Quintac3421) liquid paraffin 40.0 parts rosin-based resin 10.0 parts (tradename: Hariester L) polyisobutylene 30.0 parts (trade name: Tetrax 6T)dibutylhydroxytoluene 1.0 part 1-menthol 1.0 part felbinac 3.0 parts

The plaster was prepared in the same manner as in Example 1 except thatthe formulation was changed to the above formulation and that thethickness of the plaster layer was 180 μm, obtaining the dispersion typeplaster in which felbinac was uniformly dispersed in thesemi-solubilized state.

Example 11

The plaster was prepared in the same manner as in Example 9 except thatthe polyisobutylene was excluded from the formulation.

Example 12

The plaster was prepared in the same manner as in Example 3 except thatthe thickness of the plaster layer was 50 μm.

Example 13

The plaster was prepared in the same manner as in Example 3 except thatthe thickness of the plaster layer was 80 μm.

Example 14

The plaster was prepared in the same manner as in Example 3 except thatthe thickness of the plaster layer was 200 μm.

Example 15

The plaster was prepared in the same manner as in Example 3 except thatthe thickness of the plaster layer was 300 μm.

Comparative Example 1

styrene-isoprene-styrene block copolymer 20.0 parts (trade name:Califlex TR-1112) liquid paraffin 52.0 parts rosin-based resin 15.0parts (trade name: KE-311) polyisobutylene 5.0 parts (trade name: Tetrax4T) dibutylhydroxytoluene 2.0 parts crotamiton 5.0 parts felbinac 1.0part

The plaster was prepared in the same manner as in Example 5 except thatthe formulation was changed to the above formulation, i.e., thatcrotamiton was mixed as a solubilizer for felbinac, thus obtaining adissolution type plaster in which felbinac existed in a fullysolubilized state because of the solubilizer. In this comparativeexample, felbinac was dissolved in crotamiton and then the mixture wasadded into the aforementioned dissolved substance.

Comparative Example 2

The plaster was prepared in the same manner as in Example 5 except thatfelbinac being the medicinally effective component was excluded from theformulation.

Comparative Example 3

The plaster was prepared in the same manner as in Example 3 except thatthe thickness of the plaster layer was 30 μm.

Comparative Example 4

The plaster was prepared in the same manner as in Example 3 except thatthe thickness of the plaster layer was 350 μm.

Test Example 1

(Stability Test: Adhesive Strength)

The plasters obtained in Examples 3, 5, 7 and 10 and Comparative Example1 were evaluated in the following manner as to the stability of adhesivestrength. The adhesive strength of each plaster (the size: 10 cm×14 cm)was measured by the probe tack test method (machine used: PROVE TACKTESTER) immediately after the preparation (in the initial stage), after3-month storage at 40° C., and after 6-month storage at 40° C. Theresults obtained are shown in Table 1.

TABLE 1 Example · Comparative Adhesive strength (g) Example Initial 40°C., 3 months 40° C., 6 months Example 3 54.3 52.4 55.3 Example 5 55.755.9 53.1 Example 7 50.2 49.5 49.0 Example 10 45.2 47.3 47.0 Comparative51.5 42.8 30.7 Example 1

As apparent from the results shown in Table 1, the plasters obtained inExamples 3, 5, 7 and 10 had good stability of adhesive strength, but theplaster obtained in Comparative Example 1 showed secular decrease ofadhesive strength due to bleeding of crotamiton.

Test Example 2

(Stability Test: Hairless Mouse Skin Permeation Experiment)

The hairless mouse skin permeation test was conducted in the followingmanner, using the plasters obtained in Example 5 and Comparative Example1 immediately after the preparation and after 6-month storage at 40° C.Specifically, the plaster cut in the diameter of 10 mm was affixed tothe skin of the back peeled off of a hairless mouse (female, 7 week old)and the lamination was set in a flow through type cell with the dermisside being the receptor phase. A receptor liquid (phosphate buffer of pH7.4) was allowed to flow at the flow rate of 0.8 ml/hr and an amount offelbinac permeating into the receptor liquid was measured by use ofHPLC. The results obtained are shown in FIG. 3.

As apparent from the results shown in FIG. 3, the plaster obtained inExample 5 revealed the stable drug release ability even after the6-month storage at 40° C., and the drug release ability was stablyretained over a long period of time as against the plaster obtained inComparative Example 1.

Test Example 3

(Carrageenin-induced Paw Edema Experiment)

Male rats of Wister strain weighing approximately 135 g were used astest animals in groups each consisting of fifteen rats. Test sampleswere the plaster obtained in Example 5, the plaster obtained inComparative Example 2, and a felbinac-containing poultice commerciallyavailable (trade name: Seltouch, available from Lederle Japan Ltd.) eachcut in the size of 3 cm×4 cm. Each of the plasters (or the poultice) wasaffixed to the rear right paw of rat for four hours and thereafter wasremoved. Immediately thereafter, 0.1 ml of 1% carrageenin solution wassubcutaneously injected into the same portion to induce the reaction.The volume of paw was measured 3 hours after the induction of thereaction and an edema rate was calculated based on the volume of pawbefore the injection. The results obtained are shown in FIG. 4. Thecontrol is an example obtained without affixing the plaster (or thepoultice) to the rat.

As apparent from the results shown in FIG. 4, the plaster obtained inComparative Example 2 containing no felbinac showed no effect on thecarrageenin-induced paw edema, whereas the plaster obtained in Example 5demonstrated the strong anti-inflammatory action, the effect of whichwas equivalent to that of the commercially available felbinac-containingpoultice.

Test Example 4

(Adhesion Test)

The plasters (the size of 10 cm×14 cm) obtained in Example 9 and Example11 were respectively affixed to the left and right knees of 30 healthymale and female adults, and the adhesion and pain upon stripping waschecked about 6 hours later according to the following criteria.

[Criteria] Adhesion perfect adhesion 5 points partial peeling of corner4 points peeling of one third or more 3 points peeling of a half or more2 points complete drop 1 point Pain upon stripping no pain 5 pointslittle pain 4 points slight pain 3 points pain 2 points heavy pain 1point

Averages of scores of the 30 adults are shown in Table 2.

TABLE 2 Example Adhesion Pain upon stripping Example 9 4.6 4.4 Example11 3.9 2.8

As apparent from the results shown in Table 2, the plasters obtained inExample 9 and Example 11 both demonstrated good adhesion, but theplaster obtained in Example 9 has better adhesion and gives less painupon stripping and thus can be said as a plaster very excellent in use.

Test Example 5

(Adhesion Test)

Each of the plasters (the size 10 cm×14 cm) obtained in Examples 3, 12,13, 14 and 15 and Comparative Examples 3 and 4 was affixed to the kneesof 30 healthy male and female adults, and the adhesion was checked about6 hours later according to the following criteria.

[Criteria] Adhesion perfect adhesion 5 points partial peeling of corner4 points peeling of one third or more 3 points peeling of a half or more2 points complete drop 1 point

Averages of scores of the 30 adults are shown in Table 3.

Test Example 6

(Stability Test: Shape Retention)

The plasters (the size 10 cm×14 cm) obtained in Examples 3, 12, 13, 14and 15 and Comparative Examples 3 and 4 each were stored at 50° C. fortwo months and thereafter their shape was evaluated according to thefollowing criteria.

[Criteria]

good shape retained: ∘

slight overflow of ointment observed: Δ

heavy overflow of ointment observed: X

The results obtained are shown in Table 3.

TABLE 3 [Criteria] Example · Comparative Example Adhesion Shape Example3 4.5 ◯ Example 12 3.1 ◯ Example 13 3.8 ◯ Example 14 4.2 ◯ Example 154.1 Δ Comparative Example 3 2.3 ◯ Comparative Example 4 3.7 X

As apparent from the results shown in Table 3, the plasters obtained inExamples 3, 12, 13, 14 and 15 showed the good results of both theadhesion and the shape after the 2-month storage at 50° C., whereas theplaster obtained in Comparative Example 3 revealed insufficient adhesionand the plaster obtained in Comparative Example 4 demonstratedinsufficient shape retention after the 2-month storage at 50° C.

As described above, the present invention can achieve thefelbinac-containing plaster that retains the high drug releasecapability and sufficient pharmacological action (the anti-inflammatoryaction) over a long period, though it is the dispersion type plastercontaining no crotamiton of solubilizer, that retains the adhesion toskin in the high level over a long period, that is excellent in thestability of preparations, and that gives little skin irritation.

Accordingly, the present invention can provide the felbinac-containingplaster useful as an anti-inflammatory, analgesic plaster for externalapplication.

From the invention thus described, it will be obvious that theembodiments of the invention may be varied in many ways. Such variationsare not to be regarded as a departure from the spirit and scope of theinvention, and all such modifications as would be obvious to one skilledin the art are intended for inclusion within the scope of the followingclaims.

What is claimed is:
 1. A plaster comprising 10-40 wt % of astyrene-isoprene-styrene block copolymer, 5-30 wt % of a rosin-basedresin, 20-70 wt % of a plasticizer, and 1.1-10 wt % of felbinac as amedicinally effective component, wherein said plaster does not contain asolubilizer for said felbinac, said felbinac is uniformly dispersed in asemi-solubilized state in said plaster, solubilized felbinac andmicrocrystalline felbinac coexist in said plaster, and said plaster hasa thickness of 50-300 μm.
 2. A plaster according to claim 1, furthercomprising a backing made of a stretch polyester fabric.
 3. A plasteraccording to claim 2, wherein said stretch polyester fabric is onedemonstrating longitudinal of strength 200 g to 3 kg and a lateralstrength of 100 g to 600 g in a 30%-modulus test under measurementconditions of sample width 50 mm, sample length 200 mm, and elongationstrength 200 mm/min.
 4. A plaster according to claim 2, wherein a basicweight of said backing is 100±30 g/m².
 5. A plaster according to claim1, wherein a blending ratio of said felbinac is 3-7 wt % of the wholeplaster.
 6. A plaster according to claim 1, wherein a blending ratio ofthe whole plaster for the following is: said styrene-isoprene-styreneblock copolymer 15-35 wt %, said rosin-based resin 10-25 wt %, and saidplasticizer 30-60 wt %.
 7. A plaster according to claim 1, wherein saidplasticizer is liquid paraffin.
 8. A plaster according to claim 1,wherein said plaster has a thickness of 80-200 μm.
 9. A plastercomprising essentially of 10-wt % of a styrene-isoprene-styrene blockcopolymer, 5-30 wt % of a rosin-based resin, 20-70 wt % of aplasticizer, and 1.1-10 wt % of felbinac as a medicinally effectivecomponent, wherein said plaster does not contain crotamiton which is asolubilizer for said felbinac, said felbinac is uniformly dispersed in asemi-solubilized state in said plaster, wherein solubilized felbinac andmicrocrystalline felbinac coexist in said plaster, and said plaster hasa thickness of 50-300 μm.